According to the CDC, each year more than two million U.S. hospital patients contract nosocomial infections, and some 80,000 of them die as a result (Federal Register, 2004). With drug-resistant infections reaching epidemic levels-especially in medical facilities-the nation's researchers and drug developers face a daunting challenge in staying ahead of the threats. One infectious disease that merits much more attention is Clostridium difficile-associated disease (CDAD). CDAD is an important cause of morbidity and mortality in hospital and nursing home patients-especially with the recent characterization of an epidemic C. difficile strain that exhibits increased virulence and antibiotic resistance. Estimates of hospitalized patients who develop CDAD annually in the U.S. range up to 2.2 million. The current conservative estimated range of annual additional cost in the U.S. alone is $1 billion to $3 billion. The extremely high added costs and human suffering caused by CDAD is a national problem that is directly relevant to NIAID, as evidenced by the NIAID-AT-SBIR Phase I funding already received for this project. A new, more-effective CDAD treatment is clearly needed. Ironically, the most common identifiable predisposing factor for CDAD is antibiotic therapy. For this particular infectious disease, the conventional cure is instead the cause-especially with relapses. Clearly, alternative therapies are needed. One such promising option is the use of human monoclonal antibodies (Mabs). Mabs are potentially excellent molecules for prevention and treatment of mucosal infectious diseases such as those caused by C. difficile. Mapp Biopharmaceutical's R&D team-including key expert collaborators-has particular expertise in Mab development and combines that experience with unique, proprietary know-how in employing next-generation Mab manufacturing techniques based on the use of plants. Production of Mabs in plants has the potential to provide a cost-effective alternative to traditional and costly mammalian cell-culture manufacturing. The excellent results obtained by Mapp and its collaborator in Phase I forms the basis for this follow-on Phase II project, focused on moving the candidate Mabs selected during Phase I into pilot manufacturing, formulation, and testing/validation via IND-enabling studies in preparation for human clinical safety trials. That work will be carried out under four Specific Aims involving 1) Mab production using the plant-based system, 2) dose-response experiments, 3) production of Mabs under cGMP, and 4) completion of IND-enabling studies. The overall goal of this multi-phase SBIR project is to develop, validate, and commercialize a human Mab-based product for prevention and/or treatment of CDAD. Drug-resistant and other difficult-to-treat infections are becoming major epidemics in the nation's hospitals and long-term care facilities. One infectious disease that merits closer attention and an effort to develop improved therapeutics is Clostridium difficile-associated disease (CDAD)-a disease that adds up to $3 billion annually to our medical costs. Mapp Biopharmaceutical's expert R&D team proposes to develop and commercialize a novel, safe, low-cost monoclonal antibody- based treatment for CDAD that will be produced using plants (in place of expensive cell-culture) as a manufacturing system.